High levels of blood cholesterol and blood lipids are conditions involved in the onset of atherosclerosis. The conversion of HMG-CoA to mevalonate is an early and rate-limiting step in the cholesterol biosynthetic pathway. This step is catalyzed by the enzyme HMG-CoA reductase. It is known that inhibitors of HMG-CoA reductase are effective in lowering the blood plasma level of low density lipoprotein cholesterol (LDL-C), in man. (cf. M. S. Brown and J. L. Goldstein, New England Journal of Medicine, 305, No. 9, 515-517 (1981)). It has been established that lowering LDL-C levels affords protection from coronary heart disease (cf. Journal of the American Medical Association, 251, No. 3, 351-374 (1984)).
To varying degrees, statins interfere with and/or inhibit HMG-CoA reductase from catalyzing the conversion of HMG-CoA to mevalonate. As such, statins are collectively potent lipid lowering agents. Thus, statins are the drugs of first choice for management of many lipid disorders. One representative statin is atorvastatin.
Atorvastatin and pharmaceutically acceptable salts thereof are selective, competitive inhibitors of HMG-CoA reductase. As such, atorvastatin calcium is a potent lipid lowering compound and is thus useful as a hypolipidemic and/or hypocholesterolemic agent, as well as in the treatment of osteoporosis, BPH, diabetes and Alzheimer's disease. A number of patents have issued disclosing atorvastatin including U.S. Pat. Nos. 4,681,893; 5,273,995 and 5,969,156. Other representative statins include lovastatin, pravastatin, simvastatin and rosuvastatin.
Statin drugs share many features, but also exhibit differences in pharmacologic attributes that may contribute to differences in clinical utility and effectiveness in modifying lipid risk factors for coronary heart disease. (Clin. Cardiol. Bol. 26 (Suppl. III), III-32-III-38 (2003)). Accordingly, it would be most beneficial to provide a statin having a combination of desirable properties including (i) potent reversible inhibition of HMG-CoA reductase, (ii) the ability to produce large reductions in LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C), (iii) the ability to increase HDL cholesterol (HDL-C), (iv) relative hydrophilicity, (v) tissue selectivity (e.g., selectivity of effect or uptake in hepatic cells through selective organic ion transport), (vi) optimal pharmacokinetics or systemic bioavailability so as to minimize any potential risk of systemic adverse effects, while at the same time having enough systemic availability so that any pleiotropic effects can be observed in the vasculature with statin treatment, (vii) availability of once a day dosing, (viii) a low potential for drug-drug interactions, (ix) the ability to lower circulating very-low-density-lipoprotein (VLDL) as well as the ability to lower triglyceride levels, (x) prolonged elimination half-life to maximize effectiveness for lowering LDL-C, (xi) absence or minimal metabolism via the cytochrome P450 (CYP) enzyme system (e.g., the CYP3A4 system) so as to minimize any potential risk of drug-drug interactions when statins are given in combination with other drugs, and (xii) reduce levels of C-reactive protein (CRP).
As described below, the present invention relates to compounds and pharmaceutical compositions useful as hypocholesterolemic and hypolipidemic agents. More specifically, the present invention concerns certain potent inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (“HMG CoA reductase”). The invention further relates to methods of using such compounds and compositions to treat subjects, including humans, suffering from hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, Alzheimer's Disease, benign prostatic hypertrophy (BPH), diabetes and osteoporosis.